6-keto-delta-19-nor-derivatives of cortical hormones



United States Patent Ofl'ice 71, 12 Claims. (Cl. 260239.55)

The present invention relates to certain novelcyclopentanoperhydrophenanthrene derivatives and to the method for thepreparation thereof.

More particularly, the present invention relates to a method for makingthe novel 6-keto-A 19-nor derivatives of cortical hormones, representedby the following formulas:

Bong

In the preceding formulas R represents hydrogen or an acyl radical ofless than 12 carbon atoms; R represents hydrogen, a-methyl, fl-methyl,u-hydroxy, a-acyloXy; R together with the hydroxy at C-l7 may alsorepresent the grouping wherein A represents hydrogen or a lower alkylradical and B represents a lower alkyl, aryl or aralkyl radical,containing up to 8 carbon atoms; Y represents hydrogen, fl-hydroxy orketo. The acyl groups are derived from hydrocarbon carboxylic acidscontaining less than 12 carbon atoms, which may be saturated orunsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or

aromatic, and may be substituted by functional groups such as hydroxy,alkoxy containing up to 5 carbon atoms,

I acyloxy containing up to 12 carbon atoms, nitro, amino I or halogen.Typical ester groups are the acetate, propi- Patented July 19, 1966 Thecompounds object of our invention are obtained by the method illustratedby the following sequence of reactions:

o-orn o-orn H2O I H1C I I orn I cm A HO Y I MN R2 Y! I Nw R2 I I I A00A00 (1) H (II) C 1120 R (EH20 R 0:0 0

I I R0 RO-- H (IV) H (III) 0 O C|3H2OR In the above formulas R and Yhave the meaning heretofore indicated; R represents hydrogen, a-methylor fi-methyl and Y represents hydrogen or a keto group.

In practicing the process outlined above we start from the '3-acetate of17,20;20,21-bismethylenedioxy-A -pregnene-3fi,19-di0l, its ll-oxygenatedand/or l6-methyl substituted derivatives (I), which upon treatment withthe chromium trioxide-pyridine complex or with chromium trioxide inaqueous acetic acid solution, or in acetone in sulfuric acid medium, atroom temperature and for a prolonged period of time, preferably between24 hours and 7 days, give rise to the corresponding A-6-ketol9-nor-oom-pounds (II). When the starting material possess also ahydroxyl group at C-ll, this is also oxidized, producing the ll-ketones.Upon hydrolysis of the bismethylenedioxy group using conventionalmethods, preferably by heating with 60% formic acid, there are obtainedthe 3-acetate of A -19-nor-pregnene-3fi,l7a, 2l-triol-6,20-dione, the3-acetate of A -l9-norpreg- .nene-3B,17a,21-triol-6,11,20-trione as wellas the corregroup at C-3, there are obtained A -l9-nor-pregnene-313,1113,17a,2l-tetrol-6,204lione and its 16-rnethyl derivatives (IV).

Conventional esterification of these compounds (III and IV; R=H) withcarboxylic acid anhydrides or acid chloridesof less than 12 carbon atomsin pyridine solution produced the corresponding 3,21-diesters (III andIV; R=acyl).

By reaction of the diesters of the llfl-hydroxy-lated compounds withmesyl chloride in dimethylformamide solution and in the presence ofpyridine, at a temperature around 80 C. and for a period of time ofbetween 30 minutes and 1 hour, there are obtained the corresponding 3,21diacyloxy Mmwul) 19- nor pregnadien 170col-6,20-diones (V; R=acyl),which upon saponification with a dilute solution of potassium hydroxideor potassium carbonate in methanol, at low temperature give rise to thecorresponding free compounds (V; R=H).

In the case of compounds non-substituted at C-l6 (III, IV and V; R =H),a hydroxyl group may be introduced in such position by incubation withStreplomyces roseochromogenus in a culture medium containing peptone andcorn syrup. The l6a,l7a-diols thus obtained are converted into thecorresponding cyclic ketals or acetals by reaction with aldehydes orketones containing up to 8 carbon atoms in the presence of an acidcatalyst, such as for example perchloric or p-toluenesulfonic acids.Typical aldehydes and ketones are acetone, acetaldehyde, acetophenone,methyl ethyl ketone, cyclohexanone, diethyl ketone and the like.

Alternatively, the compounds object of our invention may be obtained bythe process illustrated by the following equation:

CH3 CHzOAc (VIII) In the above formulas R has the same meaning asheretofore indicated.

In practicing the process illustrated above, the 3-acetate of A-l9-nor-pregnene-3fi,l7a-diol-6,20-dione or its 16- substitutedderivatives (VI) was treated with iodine in the presence of calciumoxide and in mixture of tetrahydrofuran-methanol to produce thecorresponding 21-iodo derivatives, which are in turn reacted withpotassium acetate, preferably at reflux temperature, to afiord the 3,21-

diacetoxy compounds (VIII). Conventional saponification of thesecompounds produce the corresponding free compounds, which are thenincubated with an oxygenating microorganism, as indicated hereinbefore,to produce the respective llfi-hydroxylated derivatives (VIII).

From these llli-hydroxy compounds there may be obtained thecorresponding ll-keto or A -dehydro derivatives, previous protection ofthe hydroxyl groups at C-3 and C-21, by the methods previouslydescribed.

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

PREPARATION l A mixture of 6.6 g. of 16fi-methyl-pregnenolone, 2.7 g. ofp-toluenesulfonic acid and 300 cc. of acetic anhydride was submitted toa slow distillation, during 5 hours. The residue was cooled and pouredinto iced water. The product was then extracted with ether, the extractWashed successively with an aqueous solution of sodium carbonate andwater to neutral, dried and evaporated to dryness. The residue consistedof 35,20-diacetoxy-16B- methyl-A -pregnadiene, which was utilized in thefollowing step without purification.

6 g. of this crude 3fi,20-diacetoxy compound were treated with 480 cc.of a 1.2 molar solution of perbenzoic acid in benzene (2.2 molarequivalents), at room tem perature and in the dark, for 20 hours. Waterwas then added, the organic layer separated, washed with an aqueoussolution of sodium bicarbonate, then with water, dried with anhydroussodium sulfate and evaporated to dryness. The residue consisted of thecrude 35,20p-diacetoxy-l6fl-methyl-5a,6ot;l7a,20a-bis-oxido-pregnane.

This crude oxido compound was treated with 500 cc. of a 1% methanolicsolution of potassium hydroxide at room temperature for 1 hour, themixture was neutralized by addition of acetic acid, concentrated tosmall volume under reduced pressure, the product was precipitated byaddition of ice water, filtered off, washed with water, dried andrecrystallized from acetone-methanol, thus yielding16B-methyl-5a,6ot-oxido-pregnane-3 8,17adiol-20-one 3-acetate.

To 5 g. of the latter compound in cc. of glacial acetic acid, there wasadded a mixture of 5 g. of sodium iodide, 1.6 g. of sodium acetate, 320mg. of zinc and 2 drops of water. While cooling in an ice bath andstirring, there were added to the resulting mixture, 800 mg. of zincdust in small portions. The stirring was continued for 6 hours and thetemperature allowed to attain 25 C.

The reaction mixture was filtered and the filtrate diluted with icewater, alkalized -with sodium bicarbonate and extracted with ethylacetate. The extract was washed to neutral, dried over anhydrous sodiumsulfate and evaporated to dryness. Crystallization from acetone-hexaneyielded 165-methyl-A -pregnene-Sfl,17u-di0l-20-one 3-acetate.

To a solution of 4.5 g. of the latter steroid in cc. of anhydrousbenzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. ofacetic anhydride and the mixture was allowed to stand for 24 hours atroom temperature, poured into ice and water, and the resulting mixturestirred to efiect hydrolysis of the excess anhydride. The benzene layerwas separated and washed with 10% sodium carbonate solution and water.Drying, evaporation and crystallization of the residue from ether-hexaneproduced 16,B-methyl-A -pregnene3,8,17a-diol-20-one diacetate.

A suspension of 2.5 g. of the foregoing diacetate in 50 cc. of dioxanewas treated with 3 cc. of 1 N perchloric acid and then with 1 g. ofN-bromacetamideQ The N- bromoacetamide was added portionwise, withstirring, in .the course of 1 hour, in the dark and maintaining thetemperature around 15 C. The mixture was stirred for 1 hour further inthe dark at room temperature and then decolorized by the addition ofaqueous sodium bisulfite solution, 1 l. of water was added and theproduct was extracted with methylene chloride. The extract was washedwith water, dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure and at room temperature.Recrystallization from methylenechloride-hexane furnished 5a bromo-16Bmethylpregnane-3B,6, l 7a-triol-20-one 3, l 7-diacet a-te.

To a solution of 2 g. of the latter 5or-bromo-compound in 75 cc. of drybenzene were added 3 g. of lead tetraacetate and the mixture wasrefluxed for 18 hours. It was then cooled, filtered, diluted with waterand the benzene layer was separated, washed with water and the benzenewas evaporated under reduced pressure. By chromatography of the residueon neutral alumina there was obtained the Sea-bromo-l6,8methyl-6B,19-oxido-pregnane-3B,17a-diol-20-one diacetate.

A mixture of 1 g. of the last named steroid, 5 g. of zinc dust and 50cc. of ethanol was refluxed for 16 hours. It was then filtered throughcelite and the filtrate evaporated to dryness. Crystallization of theresidue from acetone-hexane yielded 16B-methyl-A -pregnene-3B,17a,19-triol-20-one 3,17-diacetate.

Example I A solution of 6 g. of the 3-monoacetate of 17,20;20,21-bismethylenedioxy-A -pregnene-3B,19-diol in 120 cc. of pyridine wasadded to a mixture of 6 g. of chromium trioxide in 120 cc. of pyridine.The reaction mixture was maintained at room temperature for 1 week; itwas then diluted with ethyl acetate, filtered through celite and thefiltrate was washed well with water, dried and evaporated to dryness.The residue was crystallized from acetonehexane, to produce the acetateof 17,20;20,2l-bismethylenedioxy-A -l9-nor-pregnen-3[3-ol-6-one.

A mixture of 4 g. of the foregoing compound and 80 cc. of 60% formicacid was heated on the steam bath for 1 hour, cooled, diluted with waterand the formed precipitate filtered off, washed with water, dried andrecrystallized from acetone-hexane to produce the 3-acetate of M -l9-nor-pregnene-3fi, l7a,21-triol-6,20-dione.

A solution of 3 g. of the latter compound in 100 cc. of methanol wastreated with 1 g. of potassium carbonate dissolved in 5 cc. of water,and the reaction mixture was kept at room temperature for 1 hour. It wasthen neutralized with acetic acid and concentrated to a small volume,diluted with water and the formed precipitate collected by filtration,to give A -19-nor-pregnene-3B,17a,

-2 l -triol-6,20-dione.

In the same manner, starting from the 3-monoacetate of17,20;20,21-bismethylenedioxy-M-pregnene-3p,19-diol- -11-one there wereobtained successively; the acetate of 17,20;20,21-bismethylenedioxy-A-19-nor-pregnen 3B- ol-6,1l-dione, the 3-acetate of A-19-nor-pregnene-3B, 17u,2l-triol-6,l1,20-trione and A-19-nor-pregnene-3,B, 17a,21-triol-6,l1,20-trione.

Example II temperature, poured into ice water and the formed.

precipitate collected by filtration, washed with water andrecrystallized from methanol to produce the acetate of 17 ,20;20,21bismethylenedioxy-A -19-nor-pregnen 3B- ol-6-one, identical to thatobtained by the method of the preceding example.

Example 111 A strain of Curvularia lunala ATCC 13935 was grown in aSabourini-glucose-agar medium (Difco). The growth obtained afterincubating for a week at 25 C. was suspended in 5 cc. of sterile water.

This suspension was divided in 5 portions of 1 cc. each which wereemployed for inoculating 5 Erlenmeyer flasks of 250 cc. capacitycontaining each 50 cc. of a culture medium of the following composition:

Distilled water to complete 1 l.

The cultures were incubated under rotatory stirring for 72 hours at 25C. The growth was homogenized for 1 minute in a Waring Blendor; 2 cc.portions of the suspension thus obtained were employed for inoculatingapproximately 100 Erlenmeyer flasks containing the same medium describedabove. The mixtures were incubated for 24 hours under rotatory stirringat 25 C. and 280 r.p.m.; to each flask there was added 0.5 cc. of asolution of 0.5 g. of [1 -l9-nor-pregnene-3/3,17a,21-triol-6,20- dionein 50 cc. of ethanol and the incubation was continued under the sameconditions for 48 hours. The contents oft he flasks were combined andextracted with four portions of methylene chloride. The combined extractwas dried over anhydrous sodium sulfate and concentra-ted at lowtemperature to a volume of 25 cc. This solution was adsorbed on 4 g. ofsilica gel and eluted with methylene chloride-ether (9:1) to produce A-l9-norpregnene-3,8,1 1,8,l7oz,21-tetrol-6,20-dione.

A mixture of 1 g. of the preceding compound, 4 cc. of pyridine and 4 cc.of acetic anhydride was kept at room temperature for 4 hours, pouredinto ice water and the formed precipitate was collected by filtration,washed with water and dried. Crystallization from acetone-hexane gavethe 3,21-diacetate of A -19-nor-pregnene-3,8,11,8,17u,2l-tetroI-6,20-dione.

Example IV A solution of 1 g. of the 3,21-diacetate of A-19-norpregnene-3B,11B,17a,21-tetrol-6,20-dione in 15 cc. of acetone wascooled to 0 C. and treated under nitrogen atmosphere and stirring withan 8 N chromic acid solution (prepared by mixing 26 g. of chromiumtrioxide with 23 cc. of concentrated sulfuric acid and dilution withWater to cc.), until the color of the reagent persisted in the mixture.It was stirred for 5 minutes further at O5 C. and diluted with water.The precipitate was filtered oil, washed with water and dried undervacuum thus producing the 3,21-diacetate of A-l9-nor-pregnene-3B,l7a,2l-triol-6,l1,20-trione.

Example V To a cold solution of 1 g. of the 3,2l-diacetate of A-19-nor-pregnene3[3,11B,l7or,2l-tetrol-6,20-dione in 12.5 cc. ofdimethyl-formamide there were added 0.42 g. of mesyl chloride and 0.5cc. of pyridine and the resulting solution was kept at 80 C. for half anhour. The reaction mixture was cooled, Water was added and the productwas extracted with ethyl acetate. The extract Was Washed with water,dried over anhydrous sodium sulfate and the solvent was evaporated.Recrystallization of the residue from acetone-hexane furnished the3,21-diacetate of A 19 nor pregnadiene 3,3,17a,21- triol-6,20-dione. Thepreceding compound was saponified in accordance with the methoddescribed in Example I, to produce 43 -l9-nor-pregnadiene-3p,17a-21-triol-6,20-dione.

7 Example VI By following the method described in Example I, 7.5 g. ofthe 3,17-diacetate of 16a-methyl-A -pregnene-3fl, 17a,19-triol-20-onewere converted into the diacetate of 16a methyl A19-nor-pregnene-3fl,17a-diol-6,20- dione.

A solution of 5 g. of the foregoing compound in 250 cc. of methanol washeated at reflux temperature for'3 hours with 1 g. of potassiumhydroxide dissolved in 2 cc. of water; it was then poured into icewater, the formed precipitate collected by filtration, washed to neutraland dried, thus afi'ording 16a-methyl-A -19-nor-pregnene-3,8,17a-diol-6,20-dione, which was esterfied with acetic anhydride inpyridine, in accordance with the method described in Example III, toproduce the 3-monoacetate of 16a-rnethyl-A -19-nor-pregnene-3,8,l7a diol6,20- dione.

A cold solution of 4 g. of the foregoing compound in 30 cc. oftetrahydrofuran and 18 cc. of methanol was treated under continuousstirring with 6 g. of pure calcium oxide, in small portions, and thenwith 6 g. of iodine. The stirring was continued at room temperatureuntil the solution turned pale yellow. The mixture was poured into icewater containing 18 cc. of acetic acid and 2 g. of sodium thiosulfate.After stirring for minutes the solution was decanted and the precipitatewas collected by filtration, thus giving the 3-monoacetate of 21-iodo-16a-metl1yl-A 19-nor-pregnene-3fi,17a-diol-6,20- dione. Thiscompound was mixed with 80 cc. of acetone and 12 g. of recently fusedpotassium acetate and the mixture was refluxed for 8 hours, concentratedto a small volume, diluted with water and extracted with ethyl acetate;the extract was washed with water, dried over anhydrous sodium sulfateand concentrated until crystallization started. The precipitate wascollected and crystallized from methanol water, thus yielding the3,21-diacetate of 16a-methyl-A -19-nor-pregnene-3B,17a,21-triol-6,20-dione.

Example VII A cold solution of 2 g. of the 3,21-diacetate of 160:-methyl-A -19-nor-pregnene-3fl,17a,21-triol-6,20 dion in 50 cc. ofmethanol was treated with 5 cc. of a 4% aqueous solution of potassiumhydroxide. The reaction mixture was kept at 0 C. for 1 hour undernitrogen atmosphere, neutralized with acetic acid and the methanoldistilled under reduced pressure.

The residue was triturated with water, the solid was filtered off,washed with water and dried under vacuum.

Crystallization from ethyl-acetate-methanol gave 16oc- The precedingcompound was incubated with a culture of Curvularia lunata ATCC 13935,by following the method described in Example III, to produce16a-methylwhich upon esterification with acetic anhydride in pyridinewas converted into its 3,21-diacetate.

Example VIII tied with a dilute solution of potassium hydroxide inmethanol, in accordance with the method described in the precedingexample, to give 16B-methyl-A-19-n0rpregnene-3,8,17a,21-triol-6,20-dione.

Upon incubation of the foregoing compound with a culture of Curvularialunata by following the method of 8 Example III, there was obtained16[3-methyl-A -19-norpregnene-3B,11 6,17a,21tetrol-6,2Odione.

Example IX By following the esteri-fication method described in ExampleIII, but using propionic, caproic, and cyclopentylpropionic anhydridesas esterifying agents, there were obtained the 3,21dipropio-nates,dicaproates and dicyclopentylpropionates of A -19-nor-pregnene-3B,l1p,17 a,21-tetrol-6,20 dione, l6u-methyl-A -19-n0rpregnene-3fi,l1B,17a,21-tetrol-6,20-dione and 16fi-methyl- A-19-nor-pregnene-3p,11,8,17a,21-tetrol-6,20-dione.

Example X Example IV was repeated but using as starting materials the3,21-diacetate of 16a-trnethyl-A-l9-norpregnene-3[3,11B,17a,21-tetrol-6,20-dione and the 3,21-dipropionate of 16/3-methyl-A 19-nor-pregnene-3B,11B,1704,21-tetrol-6,2O-dione, to produce respectively; the3,21-diacetate of 16a-methyl-A -19-nor-pregnene-3B,17a,21-triol-6,11,20-trione and the 3,21-dipropionate of 16,8 methyl-A-19-norpregnene-3,B,17a,2l-triol 6,11, 20-trione.

Example XI A culture of Streptomyces roseochromogenus ATTC 3347 wasprepared in an inclined agar medium containing 1% of glucose and 1% ofyeast extract. 1 cc. of a suspension of this culture was then used toinoculate each one of a series of 250 cc. flasks containing 50 cc. of asterilized aqueous medium of 2% peptone and 5% corn syrup, the mixtureswere then incubated in a shaking machine at 28 C. under aeration for aperiod of 24-48 hours. There was thus obtained a vegetating growingculture of Streptomyces roseochromOgenus which was used for thesubsequent incubation of the steroid.

10 mg. of A -19-nor-pregnene-3;3,11[3,17u,21-tetrol- 6,20-dione wereadded to each 50 cc. of the vegetating culture of Streptomycesresochromogenus, obtained as described above. The mixture was stirredfor 48-72 hours with aeration and then extracted several times withmethylene dichloride. The extract was washed with water, dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure.

The residue was purified by chromatography on silica gel thus giving A-19-nor-pregnene-3B,11,B,1 6a,17a,21- pentol-6,20-dione.

Example XII To a solution of 1 g. of the foregoing pentol in 50 cc. ofacetone there were added 20 drops of perchloric acid. After 1 hour atroom temperature 20 drops of pyridine were added and the resultingsolution was evaporated to dryness under reduced pressure. 30 cc. ofwater were added to the residue and it was then extracted several timeswith cc. of ethyl acetate. The combined extracts were washed toneutrality with water, dried over sodium sulfate and evaporated todryness. The residue was triturated with methanol, to produce16a,l7a-isopropylidenedioxy-A 19nor-pregnene-3B,11,8,21-triol-6,20-dione. Upon esterification of thepreceding compound with acetic, propionic and undecenoic anhydrides, inaccordance with the method of Example III, there were obtained therespective 3,21-diesters.

Example XIII By following the method described in Example IV, 1 g. ofthe 3,21-dipropionate of 16a,17a-isopropylidenedioxy-A 19nor-pregnene-3/3,1lB,21-triol-6,20-dione was oxidized with 8 N chromicacid in acetone solution to give the dipropionate of16a,17a-isopropylidenedioxy- A-19-nor-pregnene-3B,21-diol-6,11,20-trione.

Example XIV Example V was repeated but using as starting material the3,2l-diacetate of l6a-methyl-A -19-nor-pregnene- 35,11,6,17a,21-tetrol6,2O-dione, thus producing the 3,21-

In accordance with the method described in Example XI, 1 g. of A-19-nor-pregnene-3B,17a,2l-triol 6,20- dione was incubated with aculture of Streptomyces roseochromogenus to produce-M 19nor-pregnene-3/3,16a, 17ot,2l-t6tIOl-6,20-Cll0l16.

Upon treatment of the foregoing compound with acetic, propionic andcyclopentylpropionic anhydrides in pyridine solution, there wereobtained the 3,16,21-triesters i.e., 3fl,l6a,21-triacetoxy-A 19nor-pregnen-17a-ol- 6,20-dione, 3B,l6a,21-tripropionoxy-A 19nor-pregnen-17a-ol 6,20'-dione and 3 8,16a,2l-tricyclopentylpropionoxy-A-19-nor-pregnen17a-ol-6,20-dione.

Example XVI A solution of 500 mg. of A -19-nor-pregnene-3B,16a,l7a,2l-tetrol-6,20-dione in '20 cc. of chloroform was treated With l g.of acetaldehyde and 5 drops of 3 N perchloric acid and the mixture wasstirred at room temperature for 2 hours. After diluting with water thechloroform layer was separated, washed with aqueous saturated sodiumbicarbonate solution and then with water, the choloroform was distilledand the residue was crystallized from acetone-ether, to afford the16a,17a-acetalde hyde acetal of A -19-nor-pregnene3fl,16a,17a,2l-tetrol- 6,20-dione.

Example XVII By following the method described in Example I, 5 g. of the3-monoacet'ate of 16a,l7a-isopropylidenedioxy- A-pregnene-3B,19-d1iol-20-one were oxidized with chromium trioxide inpyridine, to produce the acetate of 16a, 17a-isopropylidenedioxy-A 19nor-pregnen-SB-ol- 6,20-dione.

The foregoing compound was treated with iodine in the presence ofcalcium oxide and in mixture of tetrahydrofurane-methanol, and the21-iodo derivative thus obtained was reacted with potassium acetate inacetone solution, to produce the diacetate ofl6a,17a-isopropylidenedioxy-A -19-nor-pregnene-3fi,21-diol-6,20-dione.

Example XVIII A mixture of 1 g. of A -19-nor-pregnene-3p,11,8,16a,17a,21-pentol-6,20-dione, 50 cc. of freshly distilled acetophenoneand 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1hour. The resulting mixture was washed with sodium bicarbonate solutionand with water to neutrality, then it was steam distilled and theproduct extracted with methylene chloride, The extract was dried overanhydrous sodium sulfate and evaporated to dryness. Crystallization fromacetone-hexane yielded the 1*6u,17a-acetophenonide of A500) 19norpregene-3fi,l1,8,16a,1711,21-pentol-6,20-dione. The foregoingcompound was converted into its 3,21-diacetate by reaction with aceticanhydride in pyridine.

Example XIX In accordance with the sap-onification method described inExample VII, the 3,21-diacetate of A-l9-n0r-pregnene-3,8,17a,21-trio1-6,11,20-trione and the3,21-dipropionate of 160c,17ot-iSOPIOPYlidfiIIBdiOXY-A 19norpregnene-3/3,2l-diol-6,11,20-trione were converted into therespective 'free compounds, i.e., A -19-nor-pregnene-3fl,17a,21-triol-6,11,20-trione and -1'6u,17u-isopropylidenedioxy-A-19-nor-pregnene-3fi,21-diol-6,11,20-trione.

We claim: 1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and an acylradical of less than 12 carbon atoms; R is selected from the groupconsisting of hydrogen, a-methyl, fi-methyl, ot-hydroxy, a-acyloxy; Rtogether with the hydroxyl group at C-17 represents also the grouping Owherein A is selected from the group consisting of hydrogen and a loweralkyl radical and B is selected from the group consisting of loweralkyl, aryl and aralkyl radicals containing up to eight carbon atoms; Yis selected from the group consisting of hydrogen, 8-hydroxy and keto.

2. A 19 nor-pregnene-3fl,17a,2l-triol-6,20-dione.

3. A 19 nor-pregnene-3fl,11B,17a,21-tetrol-6,20- dione.

4. 16a methyl A -19-nor-pregnene-3B,115,17a, 21-tetrol-6,20-dione.

5. A500) 19 nor-pregnene-3[3,11B,l6a,17a,21-pentol- 6,20-dione.

6. 16:1,17a isopropylidenedioxy A -19-nor'preg-Ilene-3B,11B,21-triol-6,20-dione.

7. A500) 19 nor pregnene-3fi,l7a,2l-triol-6,11,20-

' trione.

8. l6a,17u isopropylidenedioxy A -l9-nor-pregnene-3B,21-diol-6,11,20-tn'one.

9. A compound of the following formula:

CHnOR I O th wherein R is selected from the group consisting of hydrogenand an acyl radical of less than 12 carbon atoms; R is selected from thegroup consisting of hydrogen, a-methyl, B-methyl, oz-hydroxy, a-acyloxy;and R together with the hydroxyl group at C-17 represents also thegrouping wherein A is selected from the group consisting of hydrogen anda lower alkyl radical and B is selected from the 1 1' 1 2 groupconsisting of lower alkyl, aryl and aralkyl radicals References Cited bythe Examiner containing up to eight carbon atoms. NI D T P 10. M 19nor-pregnadiene-3fl,17u,21-triol- U TE STA ES ATENTS zo 3,178,419 4/1965Jeger et a1 260239.55 1 16a: methyl 5(1o),9 11) g a 5 3,206,460 9/1965Bowers 260-23955 17a,21-11l'iO1-6,20-di0116.

12. 16a,17a isopropylidenedioxy A -19-nor- LEWIS GOTTS Pnmary Exammerpregnadien-3B,21-dio1-6,20-dione. T. MESHBESHER, Assistant Examiner.

1. A COMPOUND OF THE FOLLOWING FORMULA